This proposal will demonstrate how heritable factors that influence jaw bone length and both the size and strength of jaw muscle interact to determine malocclusion phenotypes in a large population of subjects undergoing surgery to correct dentofacial deformities. Work toward completion of this proposal will be done with laboratory facilities, equipment and established clinical and analytical collaborations already available to the principle investigator. This proposal is the first to consider heritable influence of both muscle and bone to be interactive in producing variations in craniofacial growth. Translation of results from this proposal will provide a new paradigm to include the consideration of heritability into clinical diagnosis and treatment planning for patients with complex dentofacial deformities. We find that in masseter muscle, size and number of fiber types are differentially associated with the development of open and deep bite malocclusion of the vertical facial dimension. Also, fiber types differ between left and right masseter muscles in subjects with facial asymmetry, which may affect occurrence of temporomandibular joint dysfunction that is a significant source of facial pain. Both findings indicate complex relationships between growth and function of muscular and skeletal components of the face. There are recent findings for heritable influences on bone length and muscle strength phenotypes. The GIANT consortium (Genetic Investigation of ANThropometric Traits) has identified 180 variants which affect human height, and the Human Gene Map for Performance and Health-Related Phenotypes (PHRP) has summarized genes or loci which affect fiber types and muscle strength during adolescence and young adulthood. The organizing hypothesis is that gene variants for bone length and muscular performance identified in the GIANT and PHRP consortiums influence the development of masticatory muscle fiber composition and dentofacial deformations. Our goal is to identify associations between specific genetic variations and differences in growth factor expression with the development of sagittal and vertical dentofacial deformations. This proposal will identify genes associated with masseter muscle fiber-type composition in subjects with dentofacial deformities (Aim 1). This is the first such study to elaborate which factors concomitantly elicit changes in masticatory muscle fiber-type properties and associate with vertical jaw development. Variability among factors identified in Aim 1, along with genes known to associate with differences in jaw length, will be used in Aim 2 to test if polymorphisms in candidate genes contribute to phenotypic variability in dentofacial deformities and facial asymmetry. PUBLIC HEALTH RELEVANCE: About half the 1.5 million Americans with dentofacial deformities have TMD as an associated condition, but the etiology of these joint complications is not well understood. For orthodontic treatment, which comprises 8% of all dental treatments, it is not possible to provide evidence-based guidance of treatment decisions due to the lack of clinical and basic science information. New studies such as this one are needed to investigate gene and environmental interactions of musculoskeletal tissues to determine the fundamental basis for development of malocclusion and dentofacial deformities.